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Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.

ABSTRACT: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified.We identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1.We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.

SUBMITTER: Li S

PROVIDER: S-EPMC4233178 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.

Li Sichen S Chowdhury Reshmi R Liu Fei F Chou Arthur P AP Li Tie T Mody Reema R RR Lou Jerry J JJ Chen Weidong W Reiss Jean J Soto Horacio H Prins Robert R Liau Linda M LM Mischel Paul S PS Nghiemphu Phioanh L PL Yong William H WH Cloughesy Timothy F TF Lai Albert A

Clinical cancer research : an official journal of the American Association for Cancer Research 20140915 22

<h4>Purpose</h4>IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.<h4>Experimental design</h4>To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = ...[more]

PMID: 25224277

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Project description:Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.

Dataset Information

Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.

Publications

Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.

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